Analysis of the longitudinal stability of human plasma miRNAs and implications for disease biomarkers.

There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal stability of miRNAs in human plasma. Here we assessed the intraindividual longitudinal stability of miRNAs in plasma from healthy human adults, and the impact of common factors (e.g., hemolysis, age) that may confound miRNA data. We collected blood by venipuncture biweekly over a 3-month period from 22 research participants who had fasted overnight, isolated total RNA, then performed miRNA qPCR. Filtering and normalization of the qPCR data revealed amplification of 134 miRNAs, 74 of which had high test-retest reliability and low percentage level drift, meaning they were stable in an individual over the 3-month time period. We also determined that, of nuisance factors, hemolysis and tobacco use have the greatest impact on miRNA levels and variance. These findings support that many miRNAs show intraindividual longitudinal stability in plasma from healthy human adults, including some reported as candidate biomarkers for Alzheimer's disease.

Proteomic changes induced by longevity-promoting interventions in mice.

Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging.

Melanoma literacy among the general population of three western US states.

Melanoma is a significant cause of cancer death, despite being detectable without specialized or invasive technologies. Understanding barriers to preventive behaviors such as skin self-examination (SSE) could help to define interventions for increasing the frequency of early detection. To determine melanoma knowledge and beliefs across three high-incidence US states, 15,000 surveys were sent to a population-representative sample. We aimed to assess (1) melanoma literacy (i.e., knowledge about melanoma risks, attitudes, and preventive behaviors) and (2) self-reported SSE and its association with melanoma literacy, self-efficacy, and belief in the benefits of SSE. Of 2326 respondents, only 21.2% provided responses indicating high knowledge of melanoma, and 62.8% reported performing an SSE at any time in their lives. Only 38.3% and 7.3% reported being "fairly" or "very" confident about doing SSE, respectively. SSE performance among respondents was most strongly associated with higher melanoma knowledge, higher self-efficacy, and personal history of melanoma. Melanoma literacy among survey respondents was modest, with greater literacy associated with a higher likelihood of reported preventive behavior. This assessment establishes a baseline and provides guidance for public health campaigns designed to increase prevention and early detection of this lethal cancer.

Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers.

Aging manifests as progressive deteriorations in homeostasis, requiring systems-level perspectives to investigate the gradual molecular dysregulation of underlying biological processes. Here, we report systemic changes in the molecular regulation of biological processes under multiple lifespan-extending interventions. Differential Rank Conservation (DIRAC) analyses of mouse liver proteomics and transcriptomics data show that mechanistically distinct lifespan-extending interventions (acarbose, 17α-estradiol, rapamycin, and calorie restriction) generally tighten the regulation of biological modules. These tightening patterns are similar across the interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response. Differences in DIRAC patterns between proteins and transcripts highlight specific modules which may be tightened via augmented cap-independent translation. Moreover, the systemic shifts in fatty acid metabolism are supported through integrated analysis of liver transcriptomics data with a mouse genome-scale metabolic model. Our findings highlight the power of systems-level approaches for identifying and characterizing the biological processes involved in aging and longevity.

Effects of Aided Communication on Communicative Participation for People With Amyotrophic Lateral Sclerosis.

PURPOSE: Many people with amyotrophic lateral sclerosis (PALS) experience speech changes, which may interfere with participation in communication situations. This study was designed to investigate the effects of aided communication on self-rated communicative participation among PALS and the relationship between speech function and communicative participation for PALS at various stages of speech impairment and communication aid use. METHOD: Participants with amyotrophic lateral sclerosis completed an online questionnaire in which they identified their current communication methods, rated their speech function, and rated their communicative participation in various situations on a modified version of the Communicative Participation Item Bank short form. PALS who reported using aided communication rated their communicative participation under two conditions: with unaided communication only and with access to all of their communication methods. RESULTS: Communication aids appeared to support communicative participation for many participants with dysarthria. Across all levels of speech function, PALS who use aided communication reported better participation under the all-methods condition than the unaided-only condition, with the largest benefits for participants with anarthria (Revised ALS Functional Rating Scale [ALSFRS-R] speech rating = 0). Communicative participation ratings worsened with more severe speech impairment under both conditions for most levels of speech function, but PALS with anarthria (ALSFRS-R speech rating = 0) reported better participation under the all-methods condition than those who used residual speech in combination with non speech methods (ALSFRS-R speech rating = 1). CONCLUSIONS: Aided communication can help PALS continue to participate in various communication situations as their speech function deteriorates. Variability in self-rated communicative participation, even for PALS at the same level of speech function, highlights the need for an individualized approach and consideration of personal and environmental factors in augmentative and alternative communication intervention. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.22782986.

Application of 3D Modeling Software to Preoperative MRI for Prediction of Surface Area of Tissue Applied During Osteochondral Allograft Reconstruction of the Knee.

Background: Preoperative magnetic resonance imaging (MRI) is used to estimate the quantity of tissue provided for fresh osteochondral allograft (FOCA) in the knee. Use of 3-dimensional (3D) MRI modeling software for this purpose may improve defect assessment, providing a more accurate estimate of osteochondral allograft tissue required and eliminating the possibility of acquiring an inadequate quantity of tissue for transplant surgery. Purpose: To evaluate the capacity of damage assessment (DA) 3D MRI modeling software to preoperatively estimate the osteochondral allograft surface area used in surgery. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Included were 36 patients who had undergone FOCA surgery to the distal femur. Based on the preoperative MRI scans, the DA software estimated the total surface area of the lesion as well as the surface areas of each subarea of injury: full-thickness cartilage injury (International Cartilage Repair Society [ICRS] grade 4), partial-thickness cartilage injury (ICRS grade 2-3), bone marrow edema, bone loss, and bone cyst. The probability of overestimation of graft tissue areas by the DA software was calculated using a Bayes-moderated proportion, and the relationship between the prediction discrepancy (ie, over- or underestimation) and the magnitude of the DA estimate was assessed using nonparametric local-linear regression. Results: The DA total surface area measurement overestimated the actual area of FOCA tissue transplanted 81.6% (95% CI, 67.2%-91.4%) of the time, corresponding to a median overestimation of 3.14 cm2, or 1.78 times the area of FOCA transplanted. The DA software overestimated the area of FOCA transplanted 100% of the time for defect areas measuring >4.52 cm2. For defects <4.21 cm2, the maximum-magnitude underestimation of tissue area was 1.45 cm2 (on a fold scale, 0.63 times the transplanted area); a plausible heuristic is that multiplying small DA-measured areas of injury by a factor of ∼1.5 would yield an overestimation of the tissue area transplanted most of the time. Conclusion: The DA 3D modeling software overestimated osteochondral defect size >80% of the time in 36 distal femoral FOCA cases. A policy of consistent but limited overestimation of osteochondral defect size may provide a more reliable basis for predicting the minimum safe amount of allograft tissue to acquire for transplantation.

Consistency and reliability of automated language measures across expressive language samples in autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with substantial clinical heterogeneity, especially in language and communication ability. There is a need for validated language outcome measures that show sensitivity to true change for this population. We used Natural Language Processing to analyze expressive language transcripts of 64 highly-verbal children and young adults (age: 6-23 years, mean 12.8 years; 78.1% male) with ASD to examine the validity across language sampling context and test-retest reliability of six previously validated Automated Language Measures (ALMs), including Mean Length of Utterance in Morphemes, Number of Distinct Word Roots, C-units per minute, unintelligible proportion, um rate, and repetition proportion. Three expressive language samples were collected at baseline and again 4 weeks later. These samples comprised interview tasks from the Autism Diagnostic Observation Schedule (ADOS-2) Modules 3 and 4, a conversation task, and a narration task. The influence of language sampling context on each ALM was estimated using either generalized linear mixed-effects models or generalized linear models, adjusted for age, sex, and IQ. The 4 weeks test-retest reliability was evaluated using Lin's Concordance Correlation Coefficient (CCC). The three different sampling contexts were associated with significantly (P < 0.001) different distributions for each ALM. With one exception (repetition proportion), ALMs also showed good test-retest reliability (median CCC: 0.73-0.88) when measured within the same context. Taken in conjunction with our previous work establishing their construct validity, this study demonstrates further critical psychometric properties of ALMs and their promising potential as language outcome measures for ASD research.

Electrocorticography Analysis in Patients With Dual Neurostimulators Supports Desynchronization as a Mechanism of Action for Acute Vagal Nerve Stimulator Stimulation.

PURPOSE: Both vagal nerve stimulation (VNS) and responsive neurostimulation (RNS System) are treatment options for medically refractory focal epilepsy. The mechanism of action of both devices remains poorly understood. Limited prior evidence suggests that acute VNS stimulation may reduce epileptiform activity and cause EEG desynchronization on electrocorticography (ECoG). Our study aims to isolate effects of VNS on ECoG as recorded by RNS System in patients who have both devices, by comparing ECoG samples with and without acute VNS stimulation. METHODS: Ten 60-second ECoGs each from 22 individuals at 3 epilepsy centers were obtained-5 ECoGs with VNS "off" and 5 ECoGs with VNS "on." Electrocorticograps containing seizures or loss of telemetry connection artifact were excluded from analysis (total of 169 ECoGs were included). Electrocorticographs were analyzed for differences in spectral content by generating average spectrograms for "on" and "off" states and using a linear mixed-effects model to isolate effects of VNS stimulation. RESULTS: Acute VNS stimulation reduced average power in the theta band by 4.9%, beta band by 3.8%, and alpha band by 2.5%. The reduction in theta power reached statistical significance with a P value of <0.05. CONCLUSIONS: Our results provide evidence that acute VNS stimulation results in desynchronization of specific frequency bands (salient decrease in theta and beta bands, smaller decrease in alpha band) in ECoGs recorded by the RNS device in patients with dual (VNS and RNS) neurostimulators. This finding offers support for desynchronization as a theorized mechanism of action of VNS. Further research may lead to future improved neurostimulator efficacy by informing optimal stimulation programming parameters.

Extreme Sawtooth-Sign in Motor Neuron Disease (MND) suggests Laryngeal Resistance to Forced Expiratory Airflow.

OBJECTIVE: The impact of laryngeal dysfunction on airflow has not been well characterized in motor neuron disease (MND). This study aimed to detect and characterize extreme airflow oscillations informally observed during volitional cough and forced vital capacity (FVC) tasks in individuals with MND who demonstrated neurolaryngeal impairments including reduced speed and extent of vocal fold abduction compared to healthy controls during volitional cough expulsion. The extreme airflow oscillations in the MND group, when viewed as a flow-volume loop, appeared similar to the "sawtooth-sign." If the airflow oscillations are periodic in a range similar to phonation, they may reflect reduced laryngeal patency. METHODS: Volitional cough and FVC airflow data (3 trials each) from 12 participants with MND with bulbar/laryngeal involvement (3 F; ages 45-76) and 12 healthy controls (6 F; ages 41-68) were analyzed for periodicity. Percent and absolute durations of periodicity of the flow oscillations were calculated by an algorithm applied to the airflow signals. In addition, the frequency, magnitude, and kurtosis of the periodic airflow oscillations were described and compared between groups. RESULTS: In both volitional cough and FVC trials, the percent of airflow periodicity during forced expiration was significantly higher (z = 3.54) in individuals with MND, adjusted for age and sex. Periodic airflow accounted for on average 28% of the total time in participants with MND and was within a frequency range similar to phonation. Magnitude of the airflow oscillations was also larger for participants with MND (z = 3.46), and kurtosis of airflow was smaller (z = -4.70) during forced expiration, indicating persistent airflow oscillations throughout exhalation. CONCLUSIONS: The significantly larger-magnitude, lower-kurtosis, and more prominent presence of sawtooth-like airflow periodicity within a frequency range similar to phonation observed in individuals with MND with neurolaryngeal impairments suggests glottic airflow resistance during forced expiration.

Interprofessional survey on medication reconciliation activities in the US Department of Veterans' Affairs: development and validation of an Implementation Readiness Questionnaire.

BACKGROUND: Medication reconciliation (MR) can detect medication history discrepancies at interfaces-in-care and help avoid downstream adverse drug events. However, organisations have struggled to implement high-quality MR programmes. The literature has identified systems barriers, including technology capabilities and data interoperability. However, organisational culture as a root cause has been underexplored. OBJECTIVES: Our objectives were to develop an implementation readiness questionnaire and measure staff attitudes towards MR across a healthcare enterprise. METHODS: We developed and distributed a questionnaire to 170 Veterans' Health Affairs (VHA) sites using Research Electronic Data Capture (REDCap) software. The questionnaire contained 21 Likert-scale items that measured three constructs, such as: (1) the extent that clinicians valued MR; (2) perceptions of workflow compatibility and (3) perceptions concerning organisational climate of implementation. RESULTS: 8704 clinicians and staff responded to our questionnaire (142 of 170 VHA facilities). Most staff believed reconciling medications can improve medication safety (approximately 90% agreed it was 'important'). However, most (approximately 90%) also expressed concerns about changes to their workflow. One-third of respondents prioritised other duties over MR and reported barriers associated with implementation climate. Only 47% of respondents agreed they had enough resources to address discrepancies when identified. INTERPRETATION: Our findings indicate that an MR readiness assessment can forecast challenges and inform development of a context-sensitive implementation bundle. Clinicians surveyed struggled with resources, technology challenges and implementation climate. A strong campaign should include clear leadership messaging, credible champions and resources to overcome technical challenges. CONCLUSIONS: This manuscript provides a method to conduct a readiness assessment and highlights the importance of organisational culture in an MR campaign. The data can help assess site or network readiness for an MR change management programme.

The duration of spontaneous active and pushing phases of labour among 75,243 US women when intervention is minimal: A prospective, observational cohort study.

Background: Friedman's curve, despite acknowledged limitations, has greatly influenced labour management. Interventions to hasten birth are now ubiquitous, challenging the contemporary study of normal labour. Our primary purpose was to characterise normal active labour and pushing durations in a large, contemporary sample experiencing minimal intervention, stratified by parity, age, and body mass index (BMI). Methods: This is a secondary analysis of the national, validated Midwives Alliance of North America 4·0 (MANA Stats) data registry (n = 75,243), prospectively collected between Jan 1, 2012 and Dec 31, 2018 to describe labour and birth in home and birth center settings where common obstetric interventions [i.e., oxytocin, planned cesarean] are not available. The MANA Stats cohort includes pregnant people who intended birth in these settings and prospectively collects labour and birth processes and outcomes regardless of where birth or postpartum care ultimately occurs. Survival curves were calculated to estimate labour duration percentiles (e.g. 10th, 50th, 90th, and others of interest), by parity and sub-stratified by age and BMI. Findings: Compared to multiparous women (n = 32,882), nulliparous women (n = 15,331) had significantly longer active labour [e.g., median 7.5 vs. 3.3 h; 95th percentile 34.8 vs. 12.0 h] and significantly longer pushing phase [e.g., median 1.1 vs. 0.2 h; 95th percentile 5.5 vs. 1.1 h]. Among nulliparous women, maternal age >35 was associated with longer active first stage of labour and longer pushing phase, and BMI >30 kg/m² was associated with a longer active first stage of labour but a shorter pushing phase. Patterns among multiparous women were different, with those >35 years of age experiencing a slightly more rapid active labour and no difference in pushing duration, and those with BMI >30 kg/m² experiencing a slightly longer active labour but, similarly, no difference in pushing duration. Interpretation: Nulliparous women had significantly longer active first stage and pushing phase durations than multiparous women, with further variation noted by age and by BMI. Contemporary US women with low-risk pregnancies who intended birth in settings absent common obstetric interventions and in spontaneous labour with a live, vertex, term, singleton, non-anomalous fetus experienced labour durations that were often longer than prior characterizations, particularly among nulliparous women. Results overcome prior and current sampling limitations to refine understanding of normal labour durations and time thresholds signaling 'labour dystocia'. Funding: OHSU Nursing Innovation and OHSU University Shared Resources.

Methodology and preliminary data on feasibility of a neurofeedback protocol to improve visual attention to letters in mild Alzheimer's disease.

Background: Brain-computer interface (BCI) systems are controlled by users through neurophysiological input for a variety of applications, including communication, environmental control, and motor rehabilitation. Although individuals with severe speech and physical impairment are the primary users of this technology, BCIs have emerged as a potential tool for broader populations, including delivering cognitive training/interventions with neurofeedback (NFB). Methods: This paper describes the development and preliminary testing of a protocol for use of a BCI system with NFB as an intervention for people with mild Alzheimer's disease (AD). The intervention focused on training visual attention and language skills, as AD is often associated with functional impairments in both. This funded pilot study called for enrolling five participants with mild AD in a six-week BCI EEG-based NFB intervention that followed a four-to-seven-week baseline phase. While two participants completed the study, the remaining three participants could not complete the intervention phase because of COVID-19 restrictions. Results: Preliminary pilot results suggested: (1) participants with mild AD were able to participate in a study with multiple assessments per week and complete all outcome measures, (2) most outcome measures were reliable during the baseline phase, and (3) all participants with mild AD learned to operate a BCI spelling system with training. Conclusions: Although preliminary results demonstrate practical feasibility to deliver NFB intervention using a BCI to adults with AD, completion of the protocol in its entirety with more participants is needed to further assess whether implementing NFB-based cognitive intervention is justified by functional treatment outcomes. Trial registration: This study was registered with ClinicalTrials.gov (NCT03790774).

"Near Cure" treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct.

Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a "near cure") with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.

Analysis of the Associations Between the Human Fecal Microbiome and Bone Density, Structure, and Strength: The Osteoporotic Fractures in Men (MrOS) Cohort.

In preclinical models, the composition and function of the gut microbiota have been linked to bone growth and homeostasis, but there are few available data from studies of human populations. In a hypothesis-generating experiment in a large cohort of community-dwelling older men (n = 831; age range, 78-98 years), we explored the associations between fecal microbial profiles and bone density, microarchitecture, and strength measured with total hip dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) (distal radius, distal and diaphyseal tibia). Fecal samples were collected and the 16S rRNA gene V4 hypervariable region sequenced. Sequences were bioinformatically processed through the DADA2 pipeline and then taxonomically assigned using SILVA. Generalized linear models as implemented in microbiome multivariable association with linear models (MaAsLin 2) were used to test for associations between skeletal measures and specific microbial genera. The abundances of four bacterial genera were weakly associated with bone density, structure, or strength (false discovery rate [FDR] ≤ 0.05), and the measured directions of associations of genera were generally consistent across multiple bone measures, supporting a role for microbiota on skeletal homeostasis. However, the associated effect sizes were small (log2 fold change < ±0.35), limiting power to confidently identify these associations even with high resolution skeletal imaging phenotypes, and we assessed the resulting implications for the design of future cohort-based studies. As in analogous examples from genomewide association studies, we find that larger cohort sizes will likely be needed to confidently identify associations between the fecal microbiota and skeletal health relying on 16S sequencing. Our findings bolster the view that the gut microbiome is associated with clinically important measures of bone health, while also indicating the challenges in the design of cohort-based microbiome studies. © 2022 American Society for Bone and Mineral Research (ASBMR).

Risk for Reinfection After SARS-CoV-2: A Living, Rapid Review for American College of Physicians Practice Points on the Role of the Antibody Response in Conferring Immunity Following SARS-CoV-2 Infection.

BACKGROUND: The strength and duration of immunity from infection with SARS-CoV-2 are important for public health planning and clinical practice. PURPOSE: To synthesize evidence on protection against reinfection after SARS-CoV-2 infection. DATA SOURCES: MEDLINE (Ovid), the World Health Organization global literature database, ClinicalTrials.gov, COVID19reviews.org, and reference lists. STUDY SELECTION: Longitudinal studies that compared the risk for reinfection after SARS-CoV-2 infection versus infection risk in individuals with no prior infection. DATA EXTRACTION: Two investigators sequentially extracted study data and rated quality. DATA SYNTHESIS: Across 18 eligible studies, reinfection risk ranged from 0% to 2.2%. In persons with recent SARS-CoV-2 infection compared with unvaccinated, previously uninfected individuals, 80% to 98% of symptomatic infections with wild-type or Alpha variants were prevented (high strength of evidence). In the meta-analysis, previous infection reduced risk for reinfection by 87% (95% CI, 84% to 90%), equaling 4.3 fewer infections per 100 persons in both the general population (risk difference, -0.043 [CI, -0.071 to -0.015]) and health care workers (risk difference, -0.043 [CI, -0.069 to -0.016]), and 26.6 fewer infections per 100 persons in care facilities (risk difference, -0.266 [CI, -0.449 to -0.083]). Protection remained above 80% for at least 7 months, but no study followed patients after the emergence of the Delta or Omicron variant. Results for the elderly were conflicting. LIMITATION: Methods to ascertain and diagnose infections varied. CONCLUSION: Before the emergence of the Delta and Omicron variants, persons with recent infection had strong protection against symptomatic reinfections for 7 months compared with unvaccinated, previously uninfected individuals. Protection in immunocompromised persons, racial and ethnic subgroups, and asymptomatic index case patients is unclear. The durability of protection in the setting of the Delta and Omicron variants is unknown. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).

Emergency Department Visits Increase in Transition-Age Patients Empaneled in a Primary Care Network at a Major Academic Medical Center.

PURPOSE: The aim of this study is to identify important predictors of emergency department (ED) utilization within a population of transition-aged patients empaneled within a primary care network, particularly with high-risk chronic conditions of childhood (HRC). METHODS: We analyzed cross-sectional data of patients aged 12-29 within a primary care network (n = 19,989). We used negative binomial regression modeling to identify important predictors of ED visits in the last year. RESULTS: Nearly 10% (n = 1,975) of the patients had one or more identified HRCs. Our final adjusted model showed that, among others, age 18-23 years (incidence rate ratio [IRR] 1.94, 95% confidence interval [CI] 1.74-2.15), presence of a high-risk condition (IRR 1.74, 95% CI 1.54-1.96]), transfer between two primary care providers in system (IRR 1.43, 95% CI 1.18-1.72), presence of care manager (IRR 2.19, 95% CI 1.68-1.72), and public insurance status (IRR 2.85, 95% CI 2.62-3.10) were all independent predictors of higher ED utilization. Conditions associated with a high incidence of ED utilization included sickle cell anemia (IRR 5.41, 95% CI 2.78-10.54), history of transplant (IRR 2.53, 95% CI 1.11-5.80), type 1 diabetes (IRR 2.12, 95% CI 1.42-3.15), and seizure disorder (IRR 2.01, 95% CI 1.61-2.51). We estimated that for each added chronic condition, the IRR increased 1.23-fold (95% CI 1.00-1.51). CONCLUSIONS: Our results demonstrate significantly greater use of high-cost healthcare services for patients in the 18- to 23-year age group and for patients with multiple complex medical conditions. These findings prompt a call for systems-wide processes to improve the pediatric-to-adult transition process.

Marrow Stimulation Has Relatively Inferior Patient-Reported Outcomes in Cartilage Restoration Surgery of the Knee: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Multiple cartilage repair techniques are available for chondral defects in the knee. Optimal treatment is controversial. PURPOSE: To evaluate change from baseline in the 5 Knee injury and Osteoarthritis Outcome Score (KOOS) subscales among different cartilage repair techniques of the knee. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 1A. METHODS: Medline and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for randomized controlled trials with minimum 1 year follow-up reporting change from baseline KOOS (delta KOOS) subscale values. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. A meta-analysis was performed on the following surgery types: microfracture (Mfx); augmented microfracture techniques (Mfx+Augment); and culture-based therapies, including autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI). A random-effects metaregression model was used. RESULTS: A total of 14 randomized trials with a total of 775 patients were included. The KOOS Sport and Recreation (Sport) and KOOS Quality of Life (QOL) were the 2 most responsive subscales after operative intervention. Outcomes from Mfx and Mfx+Augment were not different in any of the 5 KOOS subscales (minimum P > .3). The mean delta KOOS Sport after ACI/MACI was 9.9 points greater than after Mfx (P = .021) and 11.7 points greater than after Mfx+Augment (P = .027). Longer follow-up time correlated with greater delta KOOS Sport (P = .028). Larger body mass index led to greater delta KOOS QOL (P = .045). Larger cartilage defect size correlated with greater delta KOOS Pain and KOOS Activities of Daily Living scores (P = .023 and P = .002, respectively). CONCLUSION: The KOOS Sport and QOL were the most responsive subscales after cartilage restoration surgery of the knee. Culture-based therapies (ACI/MACI) led to clinically relevant improvements in the KOOS Sport score compared with marrow stimulation and may be a more appropriate treatment in younger and more active individuals. There were no benefits to Mfx+Augment over Mfx alone in any of the KOOS subscales.

Social media utilization, preferences, and patterns of behavior in patients with gynecologic pelvic pain.

BACKGROUND: Social media is increasingly becoming a health resource for people suffering from complex and debilitating health conditions. A comprehensive understanding of how and why social media and the Internet are used among patients with chronic gynecologic pain will allow for the intentional development and incorporation of web-based tools into patient care plans. OBJECTIVE: This study aimed to determine whether gynecologic patients with pain are more likely to use social media and the Internet to understand and manage their condition than those without pain. The survey was designed to explore how gynecologic patients with and without pain use and interact with social media and other web-based health resources and the clinical, personal, and demographic factors influencing these behaviors. STUDY DESIGN: Patients presenting with a new complaint to a gynecologist at 1 of 6 Fellowship in Minimally Invasive Gynecologic Surgery-affiliated hospital systems were screened, consented, and assigned to pain and no-pain groups. Participants were surveyed about social media and Internet use, symptoms, bother, physician selection, motivation, trust, and demographic information. Survey responses were compared using the Fisher exact tests, odds ratios, and risk ratios from standard tabular analysis, univariate or multivariate tests of means, and regression analyses, as appropriate. RESULTS: Of 517 participants included in the study, 475 (92%) completed the survey, 328 (69.1%) with pain and 147 (30.9%) without pain. Study participants in the pain group reported more than double the odds of using social media than those without pain (37.8% vs 19.7%; odds ratio, 2.47; 95% confidence interval, 1.54-3.96) and triple the odds of using the Internet (88.4% vs 69.4%; odds ratio, 3.37; 95% confidence, 2.04-5.56) to understand or manage their condition. Participants with pain were more likely than those without pain to engage in social media at a higher level (3.5 vs 1.7 on a scale of 0 to 10; P<.0001), be motivated by interpersonal elements of online engagement (Hotelling's T2=37.3; P<.0001), prefer an interactive component to their online health resource (35.6% vs 24.3%; risk ratio, 1.46; 95% confidence interval, 1.00-2.20; P=.0433), be influenced by others in their choice of a gynecologist (0.37 vs 0.32 on a scale of 0 to 1; P=.009), use social media as a coping tool (38.3% vs 17%; P=.0001), trust information found on social media (31.4% vs 16.7%; P=.0033), and trust other women with the same condition, informal health resources, and personal sources more and doctors and formal health resources less (P=.0083). Participants in both groups reported higher levels of social media engagement with higher levels of symptom bother (28% increase in engagement with every doubling of bother level (P<.0001). CONCLUSION: Patients with gynecologic pain were more likely than those without pain to use social media and the Internet to understand and manage their condition. Patients with pain engaged in and trusted social media at a higher level, with engagement rising directly with bother level.

Brief report: Enhanced DRα1-mMOG-35-55 treatment of severe EAE in MIF-1-deficient male mice.

Macrophage migration inhibitory factor (MIF-1) and its homologue d-dopachrome tautomerase (MIF-2) share the common CD74 receptor and function innately to enhance severity of multiple sclerosis (MS) as well as the experimental autoimmune encephalomyelitis (EAE) model for MS. We previously demonstrated that genetically high-MIF-expressing male subjects with relapsing MS had a significantly greater risk of conversion to progressive MS (PMS) than lower-MIF-expressing males. To expand on this observation, we utilized MIF-1, MIF-2, and MIF-1/2-DUAL-deficient male mice to discern if there would be a greater contribution of these inflammatory factors in EAE mice with severe vs. moderate clinical disease signs. As shown previously, mice deficient in either MIF-1 or MIF-2 each had a ∼25% reduction of moderate EAE compared to WT mice, with significant differences in disease onset and trajectory. However, EAE induction in mice deficient in both MIF-1 and MIF-2 genes did not result in a further reduction in EAE severity. This result suggests that the two MIF homologues were likely affecting the same pathogenic pathways such that each could partially compensate for the other but not in an additive or synergistic manner. However, MIF-1-KO, MIF-2-KO, and MIF-1/2-DUAL-KO mice with severe EAE did not exhibit a significant reduction in cumulative EAE scores compared with WT mice, but the MIF-1-KO and, to a lesser extent, MIF-1/2-DUAL-KO mice did show a significant reduction in daily EAE scores over the last 3 days of observation, and MIF-2-KO mice showed a more modest but still consistent reduction over the same span. Furthermore, deletion of MIF-1 resulted in a massive reduction in the expression of EAE- and Complete Freund's Adjuvant-associated inflammatory factors, suggesting delayed involvement of the MIF/CD74 axis in promoting disease expression. To further explore modulation of MIF-1 and MIF-2 effects on EAE, we treated WT mice with moderate EAE using DRα1-mMOG-35-55, an inhibitor of CD74 that blocks both MIF-1 and MIF-2 action. This treatment reduced ongoing moderate EAE severity in excess of 25%, suggesting efficient blockade of the MIF/CD74 axis in disease-enhancing pathways. Moreover, DRα1-mMOG-35-55 treatment of mice with severe EAE strongly reversed EAE- and CFA-associated expression of inflammatory cytokines and chemokines including Tnf, Ccr7, Ccr6, Ccl8, Cxcr3, and Ccl19 in MIF-deficient mouse genotypes, and also exceeded innate MIF-1 and MIF-2 EAE enhancing effects, especially in MIF-1-KO mice. These results illustrate the therapeutic potential of targeting the disease-enhancing MIF/CD74 pathway in male mice with moderate and severe EAE, with implications for treatment of high-MIF-expressing RRMS human males at risk of conversion to progressive MS as well as those that have already transitioned to PMS.